Interpretive Handbook

Lung cancer is the leading cause of cancer-related deaths in the world. Non-small cell lung cancer (NSCLC) represents 70% to 85% of all lung cancer diagnoses. Small molecular agents that target the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) protein are approved for the treatment of locally advanced or metastatic NSCLC as a second- or third-line regimen. Subsequently, randomized trials have suggested that targeted agents alone or combined with chemotherapy may be beneficial in maintenance and first-line settings. Because the combination of targeted therapy and standard chemotherapy leads to an increase in toxicity and cost, strategies that help to identify the individuals most likely to benefit from targeted therapies are desirable.

EGFR is a growth factor receptor that is activated by the binding of specific ligands, resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately leading to cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression for many solid tumors. Targeted therapies directed to tumors harboring activating mutations within the EGFR tyrosine kinase domain (exons 18-21) have demonstrated some success in treating a subset of patients with NSCLC by preventing adenosine triphosphate (ATP)-binding at the active site. Gefitinib and erlotinib have been approved by the FDA for use in treating patients with NSCLC who previously failed to respond to the traditional platinum-based doublet chemotherapy. These 2 drugs have also recently been shown to increase progression-free and overall survival in patients who receive EGFR-tyrosine kinase inhibitor therapy as a first-line therapy for the treatment of NSCLC.

Agents such as gefitinib and erlotinib (anti-EGFR small-molecule inhibitors), which prevent ATP binding to EGFR kinase, do not appear to have any meaningful inhibitor activity on tumors that demonstrate the presence of the specific drug-resistant EGFR mutations such as T790M or small insertions in exon 20. Therefore, current data suggest that the efficacy of EGFR-targeted therapies in NSCLC is confined to patients with tumors demonstrating the presence of EGFR-activating mutations such as L858R, L861Q, G719A/S/C, or small deletions within exon 19 and the absence of a drug-resistant mutation. As a result, the mutation status of EGFR can be a useful marker by which patients are selected for EGFR-targeted therapy.